tbuckley/cabot-search huggingface dataset:
TMET-33. ELONGATION CONTROL OF MRNA TRANSLATION SUPPORTS GROUP 3 MEDULLOBLASTOMA ADAPTATION TO NUTRIENT DEPRIVATION
Authors: Alberto Delaidelli, Betty Yao, Gian Luca Negri, Yue Zhou Huang, Albert Huang, Gabriel Leprivier, Poul Sorensen
Journal: Neuro-Oncology (2022)

Abstract Group 3 affiliation and MYC genetic amplification are associated with poor life expectancy and substantial morbidity in children suffering from medulloblastoma (MB). However, the high metabolic demand induced by MYC-driven transformation sensitizes MYC-overexpressing MB to cell death under conditions of nutrient deprivation (ND). Additionally, MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, promotes survival of MYC-overexpressing tumors under ND. Interestingly, eEF2K is overexpressed in MYC-driven MB and our preliminary proteomics data highlight large-scale alterations in OXPHOS components affecting eEF2K deficient MB cells. We therefore hypothesized that eEF2K activity is required for the selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MB. We performed Multiplexed enhanced Protein Dynamic Mass Spectrometry in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. Messenger RNAs encoding multiple (9 out of 10 detected) components of the mitochondrial OXPHOS pathway are selectively translated upon eEF2K activation. Inactivation of eEF2K by genetic KO leads to the disassembly of electron transport chain (ETC) complexes I-IV without affecting mRNA levels of their respective components. Consistently, eEF2K KO MB cells display decreased mitochondrial membrane potential and 20% increased proton leak thorough the mitochondrial membrane. In addition, eEF2K inactivation results in increased Group 3 MB cell death under ND and doubles survival of MB bearing mice fed with calorie restricted diets (p&amp;lt; 0.05). Control of mRNA translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MB, likely representing an adaptive response by which MYC-driven MB cells cope with acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs as eEF2K activity appears critical under metabolic stress conditions.
NIMG-105. DEUTERIUM METABOLIC IMAGING (DMI) DETECTS A LARGER WARBURG EFFECT IN HIGH-GRADE BRAIN TUMORS AND IN IDH WILD TYPE GLIOMAS
Authors: Lauren Kim, Henk De Feyter, Robin de Graaf, Robert Fulbright, Yanning Liu, Douglas Rothman, Joachim Baehring, Nicholas Blondin, Peter Kim, Antonio Omuro, Veronica Chiang, Jennifer Moliterno, Sacit Bulent Omay, Joseph Piepmeier, Zachary Corbin
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The Warburg Effect (WE) is a metabolic change in which tumors favor glycolysis over oxidative phosphorylation and has been linked to cancer aggressiveness. Mutations in the isocitrate dehydrogenase (IDH) genes in gliomas are associated with improved outcomes. We deployed a magnetic resonance (MR) spectroscopic imaging technique coined Deuterium Metabolic Imaging (DMI) to measure the WE in multiple brain tumor types. METHODS Twenty-one patients underwent DMI, acquired on a Bruker 4T MR scanner after oral administration of 0.75g/kg of deuterated glucose. The WE was defined as the ratio of deuterated lactate, representing glycolysis, over deuterated glutamate and glutamine, representing oxidative phosphorylation. We devised an interval scale from 0 to 2 for the WE results. The Wilcoxon rank sum test was performed to detect differences between groups. RESULTS The WE measurements for the largest groups, by diagnosis, showed: glioblastoma (n= 9, mean= 1.67); astrocytoma, IDH-mutant, WHO grade 3 (n= 2, mean= 0.25); oligodendroglioma, WHO grade 3 (n= 3, mean= 0.5); low grade glioma, IDH-mutant (n= 2, mean= 0); and meningioma, WHO grade 2 (n= 2, mean= 0). The WE for high-grade tumors (n= 15, mean= 1.27) was significantly different from the WE for low-grade tumors (n= 5, mean= 0), with p= 0.010. The WE for IDH wild type gliomas (n= 9, mean= 1.67) was significantly different from the WE for IDH-mutant gliomas (n= 9, mean= 0.44), with p= 0.007. Analysis is ongoing. CONCLUSIONS DMI successfully and non-invasively detects the WE in many types of brain tumors. The WE was larger in high-grade tumors as compared to low-grade tumors, and the WE was larger in IDH wild type gliomas as compared to IDH-mutant gliomas. If validated with future studies, our results suggest that DMI is a useful tool to measure differences in the metabolism of brain tumors with different clinical behaviors.
EXTH-02. ANTI-TUMOR EFFECTS AND IN VIVO DYNAMICS OF EPCAM-DIRECTED CAR T-CELLS FOR BRAIN METASTASES FROM LUNG CANCER
Authors: Tao Xu, Philipp Karschnia, Bruno Cadilha, Sertac Dede, Michael Lorenz, Niklas Seewaldt, Elene Nikolaishvili, Katharina Müller, Jens Blobner, Nico Teske, Sigrid Langer, Hannah Obeck, Theo Lorenzini, Matthias Mulazzani, Wenlong Zhang, Hellen Ishikawa-Ankerhold, Veit R Buchholz, Marion Subklewe, Niklas Thon, Andreas Straube, Joerg-Christian Tonn, Sebastian Kobold, Louisa von Baumgarten
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Lung cancer patients are at a high risk for brain metastases, and affected patients frequently succumb to their intracranial disease. Chimeric Antigen Receptor (CAR) T-cells emerged as a powerful cell-based immunotherapy for hematological malignancies; however, it remains unclear whether CAR T-cells represent a viable therapeutic avenue for brain metastases. METHODS A fully immunocompetent, orthotopic cerebral metastasis model was established in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning microscopy. This approach enabled the in vivo-characterization of fluorescent CAR T-cells and tumor cells on a single-cell level over weeks. Intraparenchymal injection of EpCAM-expressing Lewis lung carcinoma cells was performed, and EpCAM-directed CAR T-cells (EpCAMCAR T-cells) were injected into the adjacent brain parenchyma after brain tumor formation. RESULTS All mice had visible tumor take with rapidly growing lesions following intracranial tumor cell injection. In mice treated with EpCAMCAR T-cells, we observed substantial CAR T-cell accumulation within the tumor compared to controls treated with undirected T-cells. This was paralleled by lower velocities of EpCAMCAR T-cells, characterizing antitumor cytotoxicity due to ‘immune cell’-‘tumor cell’ contacts. Consequently, treatment with EpCAMCAR T-cells resulted in reduced tumorous growth as determined per in vivo-microscopy (median tumor area on day 10: 1.8 versus 10.8 mm2; p=0.001) and immunohistochemistry of excised brains. However, the number of intratumoral EpCAMCAR T-cells within the tumor markedly decreased during the observation period, pointing towards insufficient persistence. Accordingly, survival was prolonged in mice receiving EpCAMCAR T-cells but long-lasting remission was rare (median survival: 15 versus 13 days; p=0.012). No CNS-specific or systemic toxicities of EpCAMCAR T-cells were encountered. CONCLUSION Our findings indicate that EpCAMCAR T-cells injected into the cerebral parenchyma may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Strategies improving the CAR T-cell persistence within brain metastases are warranted to further boost the therapeutic success.
PATH-45. INTRAEPIGLIOM - RAPID SEQUENCING-BASED DIAGNOSIS OF BRAIN TUMORS
Authors: Carolin Kubelt, Björn Brändl, Alena van Bömmel, Christian Rohrandt, Gaojianyong Wang, Maximilian Evers, Stephan Kolkenbrock, Derek Wong, Dominik Danso, Andre Maicher, Sönke Friedrichsen, Martin Proescholdt, Markus Riemenschneider, Ulrich Jetzek, Alexander Meissner, Stephen Yip, Helene Kretzmer, Michael Synowitz, Franz-Josef Müller
Journal: Neuro-Oncology (2022)

Abstract The intraoperative diagnosis of brain tumors remains a clinical challenge despite recent technological advances. The current clinical practice differentiates non-surgical brain tumors from those preferably treated with cytoreductive surgery employing intraoperative frozen section diagnostics. A detailed molecular diagnosis required for this classification task within the timeframe of a routine neurosurgical procedure is currently unavailable. We have analyzed a clinical cohort of several brain tumor entities using Nanopore long-read sequencing on two Oxford Nanopore Technologies sequencing platforms (MinION, PromethION). Since currently available molecular cancer classifiers such as the DKFZ methylation profiling classifier cannot be readily adapted to real-time sequencing analysis, we implemented a novel algorithm (MethyLYZR) to predict the underlying cancer type. Publicly available Illumina Infinium array data were used to train the classifier to distinguish 91 brain tumor classes. For validation of classification accuracy, we conducted a comprehensive validation strategy. Both nanopore platforms could sequence more than 5,000 pre-selected CpG within less than 20 minutes for most of our samples. When combining an optimized library preparation protocol with the time used for sequencing the minimal number of CpGs needed for classification, we saw sample-to-answer times of less than 1 hour – in many cases within 45 minutes - from receiving a fresh biopsy to a robust cancer type prediction. Comparing actual and predicted diagnoses resulted in a favorable error rate, indicating potentially highly clinical validity. Our real-time based molecular diagnostic algorithm enables, in most cases, a reliable diagnostic call within the timeframe of a typical neuro-oncological surgery. MethyLYZR as a predictive tool may allow us to adjust the surgical strategy and deliver the prognosis to our patients right after surgery, thus allowing for as-of-yet unexplored opportunities for the intraoperative application of individualized therapeutic modalities.
SURG-17. PROGNOSIS IN IDH-MUTANT GLIOMA: THE ROLE OF EXTENT-OF-RESECTION, AGE AND TUMOR GRADE
Authors: Thijs van der Vaart, Karin van Garderen, Maarten Wijnenga, Erik Jan Dubbink, Pim French, Marion Smits, Clemens M F Dirven, Johan Kros, Arnaud Vincent, Martin van den Bent
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Evidence suggests that smaller residual tumor volumes after initial surgery are associated with longer survival in patients with astrocytoma, IDH-mutant, grade II. For IDH-mutant glioma of higher grade but also for oligodendroglioma, IDH-mutant, and 1p/19q codeleted, the impact of residual tumor volume on survival is unclear. This could be related to the limited follow-up of patients with oligodendroglioma that typically have long overall survival. We expanded a previously published series of patients increase the duration of follow-up and the spectrum of tumor grades. METHODS Single center observational cohort study of patients with adult-type diffuse glioma, IDH-mutant, all WHO-2021 grades, from 2003 to 2021 . Molecular characteristics were assessed by next-generation targeted sequencing. Tumor volumes were calculated by semi-automatic 3D segmentation on pre- and postoperative MRI-scans. Associations between prognostic factors and survival were assessed using univariate and multivariate Cox proportional hazards models. RESULTS 384 patients with IDH-mutant glioma (174 oligodendroglioma, 212 astrocytoma) were followed for a median of 7 years. Median age at diagnosis was 41 years (IQR 33 – 55). Significant prognostic factors for survival were Karnofsky performance status, 1p19q-status and post-operative tumor volume. Smaller post-operative tumor volume was associated with better survival, both in astrocytoma and oligodendroglioma. Age, tumor grade and MRI-contrast enhancement were not associated with survival. CONCLUSION Lower residual tumor volume after first surgery is a strong prognostic factor in all IDH-mutant glioma subgroups, even in patients with very small residual tumor. Importantly, age and histological tumor grade were not significantly associated with survival. The data serves as further support for optimal initial resections of tumors suspected for IDH-mutant glioma, also in oligodendroglioma.
CTNI-05. MOLECULAR ANALYSIS OF THE PHASE I D-TERMINED TRIAL ON CONCURRENT AND ADJUVANT TEMOZOLOMIDE WITH MINOCYCLINE IN NEWLY DIAGNOSED HIGH-GRADE GLIOMA
Authors: William McKean, Kenneth Boucher, Jingye Yang, Karthik Sonty, Randy Jensen, Dennis Shrieve, Karen Salzman, Brett Johnson, Melissa Thomas, Whitney Moss, Amanda Behunin, Elizabeth Prystas, Howard Colman, Adam Cohen
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Minocycline blocks microglial TNF signaling and downstream NF-κB activation, which reduces the mesenchymal phenotype in preclinical models of GBM. Primary analysis of the D-TERMINED trial identified a maximal tolerated dose (MTD) of oral minocycline at 150 mg BID in combination with temozolomide and radiation. In the overall population, the secondary objective of improved PFS was not met. Here, response is further stratified by biomarkers delineating mesenchymal subtype (OLIG2, CD44), microglial activation (IBA-1), and NF-κB signaling (P-p65). METHODS Patients with newly diagnosed high-grade glioma received continuous oral minocycline during concurrent chemoradiation and adjuvant temozolomide. Twenty patients were included in the MTD efficacy population. Within this cohort, immunohistochemistry for OLIG2, CD44, IBA-1, and P-p65 was performed on nineteen patient tumor samples. For each biomarker, the mean percent positivity or number/HPF was compared between patients who exceeded or did not exceed expected PFS. Spearman correlation coefficients were also generated for pairwise comparison of these biomarkers. RESULTS In patients with high PFS, 12.7% of tumor cells were positive for OLIG-2, 36.5% for CD44, and 23.9% for P-p65, with 41.7 cells/HPF positive for IBA-1. Comparatively, in patients with low PFS, 9.4% of tumor cells were positive for OLIG-2 (p = 0.59), 34.1% for CD44 (p = 0.77), and 22.3% for P-p65 (p = 0.85), with 31.1 cells/HPF positive for IBA-1 per HPF (p = 0.38). The only biomarkers demonstrating significant relationship were P-p65 and IBA-1, with a rank correlation of 0.637 (p = 0.007). CONCLUSIONS Exploratory analysis of D-TERMINED concludes that OLIG-2, CD44, IBA-1, and P-p65 are not predictive of improved PFS within high-grade glioma patients treated with SOC and minocycline. Concurrent use of minocycline with chemoradiation is therefore not indicated in these or unselected populations. Significant correlation is seen between IBA-1 and P-p65, biomarkers of microglial activation and NF-κB signaling. SPONSORSHIP: Funding provided by the Musella Foundation and NIH grant P30CA042014.
QOL-05. OPIATE UTILIZATION AND PREDICTIVE FACTORS IN PATIENTS UNDERGOING SURGERY FOR GLIOMAS
Authors: Phuong Deleyrolle, Abeer Dagra, Shahd Mohamed, Muhammad Abdul Baker Chowdhury, Nina McGrew, Maryam Rahman
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Opiate dependence is a national crisis. The use of opiate in patients diagnosed with gliomas undergoing surgery is not well understood. OBJECTIVE The objective of this study was to evaluate opiate use in patients undergoing surgery for gliomas and risk factors for prolonged opiate use. METHODS A retrospective chart review was conducted on patients ≥ 18 years who underwent surgery for glioma from 1/2016 to 1/2020. Clinical data was collected and opiate dose was calculated as morphine equivalent dose (MED). Clinical data prior to surgery, during surgery, and post-operative setting were collected. Descriptive statistics (means, frequencies, and percentages) were used to characterize the study population. Chi-square, with Fisher’s exact test, was used to determine associations for categorical variables. Linear and negative binomial regression models were used to predict MED doses with patient characteristics. RESULTS 180 patients were included in the analysis. The median MED at the time of surgery was 23.5 (IQR: 1.6, 72.5). 57 patients (46.04%) continued to take opiates after surgery. During adjuvant treatment the median MED was 45 (IQR: 45- 45) and the median length patients remaining on opiates was 59 days (IQR: 33- 168.5), with the longest usage being 1459 days. History of substance use, chronic headaches and other pain syndromes were not associated with increased use of opiates at the time of surgery. However, these factors were associated with higher morphine use after surgery. Male had a slightly higher dose (&amp;lt; 0.001) at the time of surgery compared to women. Peri-operative use at the time of surgery did not predict the MED and length of opiate use as outpatient. CONCLUSION Nearly half of the patients continued to use opiate beyond the peri-operative setting as outpatient at a higher median MED on median period of 59 days suggesting opportunities for improvement in opiate management post operatively.
CTNI-55. INITIAL TEMOZOLOMIDE MONOTHERAPY WITHOUT RADIOTHERAPY MIGHT BE OF LIMITED BENEFIT IN THE TREATMENT OF ASTROCYTOMA, IDH-MUTANT, CNS WHO GRADE 2 AND 3
Authors: Jonathan Weller, Sophie Katzendobler, Jens Blobner, Frederic Thiele, Hannes Becker, Stefanie Quach, Rupert Egensperger, Maximilian Niyazi, Bogdana Suchorska, Niklas Thon, Michael Weller, Joerg-Christian Tonn
Journal: Neuro-Oncology (2022)

Abstract QUESTION The role of temozolomide chemotherapy alone in isocitrate dehydrogenase (IDH)-mutant astrocytomas has not been conclusively determined. Recent studies have linked temozolomide therapy with induction of hypermutation and poor clinical course in some IDH-mutant gliomas. METHODS In this retrospective, single-center study, 183 patients with astrocytoma, IDH-mutant, CNS WHO grade 2 or 3 diagnosed between 2003 and 2019 were included. Patients initially monitored by means of a wait-and-scan strategy, or treated with radiotherapy alone, or receiving temozolomide alone, after histological sampling through biopsy or tumor resection, were studied. Progression-free and overall survival was analysed. A matched-pair analysis accounting for post-surgical tumor volume was conducted. RESULTS Initial T2 tumor volume and WHO grade were associated with survival in univariate analyses (p &amp;lt; 0.01). The proportion of WHO grade 2 gliomas was highest in the wait-and-scan cohort (p &amp;lt; 0.01). Tumor volumes were largest in the temozolomide cohort (p &amp;lt; 0.01). Radiotherapy was associated with longer progression-free survival than temozolomide (6.2 vs 3.4 years, p = 0.02) and wait-and-scan strategies (6.2 vs 4 years, p = 0.03). Patients treated with radiotherapy showed longer overall survival than patients treated with temozolomide (14.4 vs 10.7 years, p = 0.02). Survival was longer in patients initially monitored by means of a wait-and-scan strategy than in patients treated with temozolomide (not reached vs 10.7 years, p &amp;lt; 0.0001). The same association was seen in a subgroup analysis of WHO grade 2 astrocytomas (p = 0.02) and by trend in a matched pair analysis (p = 0.09). CONCLUSION The results suggest superiority for progression-free survival of radiotherapy alone over temozolomide alone or wait-and-scan strategies and for overall survival of radiotherapy alone and wait-and-scan therapies over temozolomide in IDH-mutant WHO grade 2 and 3. Recent study results indicating that temozolomide might compromise prognosis in some patients with IDH-mutant gliomas might be supported by our data.
EXTH-80. THE MOLECULAR FUNCTION AND THE THERAPEUTIC POTENTIAL OF MICRORNA-211 IN GROUP 3 MEDULLOBLASTOMAS IN CHILDREN
Authors: Menglang Yuan, Keisuke Katsushima, Rudramani Pokhrel, Bongyong Lee, Stacie Stapleton, George Jallo, Eric Raabe, Charles Eberhart, Ranjan Perera
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma is a central nervous system tumor that primarily affects children and requires aggressive therapy. Patients often suffer from treatment-related side effects, and treatment-resistant recurrences are common, with high mortality rates. There are four major molecular MB subgroups (Wnt- and Shh-activated MBs G3 and G4 MBs). G3 MB is the most aggressive subtype, and the diagnosis and management remain challenging. Medulloblastomas develop through various genetic, epigenetic, and noncoding (nc) RNA-related mechanisms. However, the roles played by ncRNAs, (microRNAs, long noncoding RNAs, circular RNAs, etc.) in MB development remain poorly defined. Here we address this knowledge gap with an exemplar microRNA, microRNA 211 (miR-211) implicated in G3 MB development and progression. Our preliminary results support that miR-211 is an attractive therapeutic agent to treat this aggressive MB subtype. miR-211 is significantly downregulated in medulloblastoma cell lines compared to normal cerebellum, underscoring its important role as a therapeutic agent and a biomarker. miR-211 ectopic expression in G3 MB cells significantly reduced cell proliferation and 3D colony formation and induced apoptosis. In vivo, miR-211force-expression in G3 MB cells injected into mouse cerebellum produce smaller tumors than those derived from parental cells. We identified that Long-chain-fatty-acid—CoA ligase 4 (ACSL4), and the oncogene Ras-related protein Rab22A are miR-211 targets genes for G3 medulloblastomas. The preliminary results of this study are encouraging and will provide a pre-clinical foundation for further therapeutic testing.
NCOG-32. PROGNOSTIC SIGNIFICANCE OF PREOPERATIVE NEUTROPHILIA AND LEUKOCYTOSIS IN CNS LYMPHOMA
Authors: Osaama Khan, Matt Ordon, Will Gibson
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE The purpose of this study is to assess the prognostic value of preoperative neutrophilia and leukocytosis in a retrospective analysis of patients presenting with biopsy proven primary CNS lymphoma (PCNSL). This research is an extension of the growing body of evidence that preoperative hematologic values correlate with overall and progression free survival amongst solid tumors, including those involving the central nervous system. Methodology: Retrospective analysis of 50 patients with biopsy proven PCNSL. Preoperative complete blood counts (CBC) were collected alongside other clinical data including imaging characteristics (focal versus multifocal), molecular subtype, and neutrophil-leukocyte ratio (NLR). Survival time starting at time of biopsy was evaluated using Cox proportional hazard models and log-rank tests. RESULTS 32 patients met eligibility criteria. Based upon the early data, only the NLR showed statistical significance on univariate analysis (HR 1.092 P=.002 CI 1.06-1.15) Multivariate analysis failed to show a statistical relationship when the independent variables age at diagnosis, preoperative leukocytosis, ANC/ALC, and WBC. The NLR approached statistical significance with multivariate analysis (HR 1.17 P= .053 CI .99-1.57). Molecular subtyping and imaging characteristic analysis is ongoing, and is not included in this analysis (including GCB subtype, MYC gene mutation). Future Direction: Studies like ours are necessary to ensure a cheap, repeatable, and universally available test for PCNSL patients. Preliminary analysis showed a trend towards significance when evaluating the NLR on multivariate analysis. More data is required to further elucidate these findings. Analysis is ongoing and will include other prognostic variables, including molecular profile and imaging characteristics.